A Trial to Evaluate the Efficacy, Safety & Tolerability of Brexpiprazole in the Maintenance Treatment of Adults With Major Depressive Disorder

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A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Brexpiprazole as Adjunctive Therapy in the Maintenance Treatment of Adults With Major Depressive Disorder

Time-to-Relapse in symptoms of Major Depressive Disorder (MDD) [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to week 46 or early termination ]

Assessed with Clinical Global Impression - Severity of Illness (CGI-S) Results. Score ranges from 1 to 7, with a score of 7 being a worse outcome than a score of 1.

Secondary Outcome Measures :

Change from Phase A baseline in Sheehan Disability Scale (SDS) mean total score at Week 46 [ Time Frame: Up to 46 weeks; from baseline visit at Day 1 to week 46 or early termination ]

When applicable, the change from phase A baseline in SDS mean total score to the last observation carried forward (week 46). Score ranges from 0 to 10, with a score of 10 being worse than a score of 0.

Time-to-Functional Relapse in symptoms of MDD [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Assessed with Sheehan Disability Scale. Score ranges from 0 to 10, with a score of 10 being worse than a score of 0.

Time-to-Relapse in symptoms of MDD [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Assessed with MADRS criteria. Scale ranges from 0 to 60 with a higher score indicating worsening symptoms of depression.

Time-to-Relapse in symptoms of MDD [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Assessed with CGI-S criteria. Score ranges from 1 to 7, with a score of 7 being a worse outcome than a score of 1.

Time-to-relapse in symptoms of MDD [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Assessed with hospitalization for depression

Time-to-Relapse in symptoms of MDD [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Assessed with lack of efficacy

Time-to-Relapse in symptoms of MDD [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Assessed with active suicidality

Percentage of subjects who relapsed based on MADRS criteria [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Scale ranges from 0 to 60 with a higher score indicating worsening symptoms of depression.

Percentage of subjects who relapsed based on CGI-S criteria [ Time Frame: Up to 26 weeks; from baseline visit to Week 46 or Early Termination ]

Score ranges from 1 to 7, with a score of 7 being a worse outcome than a score of 1.

Percentage of subjects who relapse by hospitalization for depression [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Percentage of subjects who relapsed by discontinuation due to lack of efficacy or worsening depression [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Percentage of subjects who relapsed by active suicidality [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Based upon MADRS and/or C-SSRS criteria

Percentage of subjects maintaining remission [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Mean change from randomization in MADRS total score [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Mean change from randomization in CGI-S score [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Change from randomization in each of the SDS individual item scores (LOCF) [ Time Frame: Up to 26 weeks; from baseline visit at Week 20 to Week 46 or Early Termination ]

Score ranges from 0 to 10, with a score of 10 being worse than a score of 0.

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Layout table for eligibility information

Ages Eligible for Study:

18 Years to 65 Years (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Subjects with both a diagnosis of recurrent major depressive disorder, and in a current major depressive episode of ≥ 8 weeks in duration, as defined by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and confirmed by both the Mini International Neuropsychiatric Interview (MINI) and an adequate clinical psychiatric evaluation.

Subjects must have reported a history for the current major depressive episode of an inadequate response to 1 or 2 adequate antidepressant treatments, and subjects must currently be taking a protocol-mandated antidepressant treatment at an adequate dose and duration, and most not have reported ≥ 50% improvement. For subjects who are currently on an adequate dose of protocol-mandated antidepressant therapy (ADT), but for an inadequate duration, can use the screening period to achieve adequate duration. At Phase A baseline visit, all subjects must have either 2 or 3 documented inadequate responses to antidepressant treatment in total for the current episode as defined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ)

Subjects with a Hamilton Rating Scale for Depression (HAM-D17) total score ≥ 18 at the screening visit, and Phase A baseline visits.

Subjects willing to discontinue all prohibited psychotropic medications to meet protocol-required washouts prior to and during the trial period.

Exclusion Criteria:

Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving investigational medicinal product (IMP).

Sexually active males or females of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of IMP.

Subjects who report treatment with adjunctive antipsychotic medication with an antidepressant for a minimum of 3 weeks during the current major depressive episode

Subjects who report allergies or an intolerability (lifetime treatment history) to trial-provided ADTs that have not been prescribed to the subject during the current major depressive episode.

Subjects who have received ECT for the current major depressive episode

Subjects who have had an inadequate response to ECT at any time in the past or who have had a vagus nerve stimulation or deep brain stimulation device implanted at any time for the management of treatment-resistant depression. Subjects who have had transcranial magnetic stimulation during the current major depressive episode.

Subjects with a current need for involuntary commitment or who have been hospitalized within 4 weeks of screening for the current major depressive episode.

Subjects with a primary DSM-5 diagnosis of:

Schizophrenia Spectrum and Other Psychotic Disorders

Bipolar and Related Disorders

Obsessive Compulsive Disorders

Feeding and Eating Disorders

Neurocognitive Disorders

Panic Disorder

Post-Traumatic Stress Disorder

Subjects with a current DSM-5 diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder or intellectual disability.

Subjects experiencing hallucinations, delusions, or any psychotic symptomatology in the current major depressive episode

Subjects receiving new onset psychotherapy (individual, group, marriage or family therapy) within 42 days of screening or at any time during participation in the trial

Subjects who have met DSM-5 criteria for substance use disorder (moderate or severe) within the past 60 days; including alcohol and benzodiazepines, but excluding nicotine

Subjects with hypothyroidism or hyperthyroidism (unless condition has been stabilized with medications for at least the past 90 days) and/or an abnormal result for free T4 at screening.

Subjects with diabetes mellitus (IDDM and non-IDDM) are ineligible for the trial unless their condition is stable and well-controlled.

Subjects with uncontrolled hypertension (DBP > 95 mmHg) or symptomatic hypotension, or orthostatic hypotension which is defined as a decrease of ≥ 30 mmHg in SBP and/or decrease of ≥ 20 mmHg in DBP after at least 3 minutes standing compared to the previous supine blood pressure OR development of symptoms.

Subjects with known ischemic heart disease or history of myocardial infarction-or congestive heart failure (whether controlled or uncontrolled)

Subjects with epilepsy or a history of seizures, except for a single seizure episode

Subjects with a positive drug screen for cocaine or other drugs of abuse (excluding known prescription stimulants and other medications and marijuana). Detectable levels of alcohol, marijuana, barbiturates, or opiates in the drug screen are not exclusionary if, in the investigator's documented opinion, the subject does not meet DSM-5 criteria for moderate to severe substance use disorder and the positive test does not signal a clinical condition that would impact the safety of the subject or interpretation of the trial results, and participation is agreed to by the medical monitor prior to treatment.

Treatment with an MAOI within 14 day prior to the first dose of IMP in Phase A.

Use of benzodiazepines and/or hypnotics (including non-benzodiazepine sleep aids) within 7 days prior to first dose of IMP in Phase A.

Use of varenicline within 5 days prior to the first dose of IMP in Phase A.

Use of oral (or immediate release intramuscular) neuroleptics within 7 days prior or long-acting approved neuroleptics ≤ 1 full cycle plus 1/2 cycle prior to the first dose of IMP in Phase A.

Subjects who would be likely to require prohibited concomitant therapy during the trial.

Subjects who have been exposed to brexpiprazole in any prior clinical trial or has received commercial brexpiprazole (Rexulti).

Subjects with a history of neuroleptic malignant syndrome or serotonin syndrome.

Subjects with a history of true allergic response to more than one class of medications

Prisoners or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.

Subjects who participated in any clinical trial within the last 60 days or who participated in more than 2 clinical trials within the past year